DESCRIPTION (applicant's description): The fibulins are an emerging family of extracellular matrix proteins characterized by the presence of tandem arrays of calcium-binding epidermal growth factor-like modules and a common C-terminal globular domain. Five members have been identified to date and they belong to two subgroups. The first two members, fibulin-1 and -2, are more related to each other by sequence identity and modular structure than to the three recently described members, fibulin-3, -4 and -5. All fibulins, except for fibulin-3, are highly abundant in the heart and blood vessel walls and thus may play essential roles in the cardiovascular system. Our laboratory first identified fibulin-2 and has subsequently studied fibulin-1 and -2 extensively. We and others have shown that fibulin- 1 and -2 are prominent components of heart septa and valves as well as aorta, pulmonary artery, and various large and small blood vessels. Fibulin-1 and -2 have also been shown to be present in the elastic fibers of the blood vessel walls where they colocalize with endostatin, the angiogenesis inhibitor. During embryonic development, fibulin-1 and -2 are highly specific markers for endocardial mesenchyme and smooth muscle cells of various types of blood vessels. The expression patterns of flbulin-1 and -2 overlap but there are distinct temporal and spatial differences. A critical role for fibulin-1 in blood vessel formation is demonstrated by our recent work showing that mice lacking fibulin- 1 are perinatally lethal as a result of massive bleeding. In this renewal application, we plan to continue studying the biological roles of fibulin-1 and fibulin-2 using biochemical approaches and transgenic mice generated by gene targeting, and to begin investigating the molecular mechanisms by which the cell-type specific expressions of fibulin genes are controlled. In addition, we propose to use flbulin-1 and -2 genes as markers to study in detail the development of heart septa and valves, great vessels and coronary blood vessels. The proposed studies will provide insights into the role of fibulins in human disease and the mechanism of cardiovascular development.